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Torpedo Maculopathy Associated with NEXMIF Mutation.

ABSTRACT: Mutations in the neurite extension and migration factor (NEXMIF) gene are associated with X-linked intellectual disability. Thus far, all males reported with NEXMIF mutations have mild to profound intellectual disability with varying combinations of autistic features, poor or absent speech, epilepsy, facial dysmorphism, and strabismus. Affected females tend to have milder intellectual disability but severe, drug-resistant epilepsy. Here, we present a 32-month-old boy with a novel de novo frameshift NEXMIF pathogenic variant (p.Glu375ArgfsX21) who has mild motor delay, language delay, autistic features, and strabismus. In addition to these commonly described findings of NEXMIF mutations, his fundus exam revealed a very rare ophthalmologic abnormality, torpedo maculopathy. This finding has not previously been reported with NEXMIF mutation; however, on literature review, 7/15 males with NEXMIF mutations had other ophthalmologic abnormalities. This patient expands the phenotypic spectrum for males with NEXMIF mutations and suggests that NEXMIF may play an important role in ocular development.

SUBMITTER: Alarcon-Martinez T

PROVIDER: S-EPMC6738190 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Torpedo Maculopathy Associated with NEXMIF Mutation.

Alarcon-Martinez Tuğba T Khan Ayesha A Myers Kenneth A KA

Molecular syndromology 20190315 4

Mutations in the neurite extension and migration factor (NEXMIF) gene are associated with X-linked intellectual disability. Thus far, all males reported with NEXMIF mutations have mild to profound intellectual disability with varying combinations of autistic features, poor or absent speech, epilepsy, facial dysmorphism, and strabismus. Affected females tend to have milder intellectual disability but severe, drug-resistant epilepsy. Here, we present a 32-month-old boy with a novel d ...[more]

PMID: 31602197

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Project description:ObjectiveTo report a case of torpedo maculopathy with multimodal fundus imaging methods, and apply the choroid vascularity index to quantitatively describe the choroidal structural changes in torpedo maculopathy.Case presentationAn asymptomatic 41-year-old Chinese woman with an incidentally found yellowish-white macular lesion in her left eye was referred to our hospital. She was unaware of any prior medical conditions. The best corrected visual acuity (BCVA) was 20/20 OD and 20/25 OS, respectively. Fundus exam of her left eye revealed a well-circumscribed torpedo-like hypopigmented lesion in the macula region, and the tapered edge directed toward the fovea. Pigment deposition could be seen in the inferotemporal portion of the torpedo lesion. Fluorescein angiography showed the corresponding window defect without leakage and fundus autofluorescence demonstrated low signal throughout the lesion. Enhanced depth imaging optical coherence tomography revealed outer retinal attenuation, subretinal cavitation, subtle inner choroidal excavation and thinning of outer nuclear layer. The diagnosis of torpedo maculopathy was clinically made. Choroidal vascularity index (CVI) and sub-foveal choroidal thickness (SFCT) were applied to display changes of choroidal structure. The results implied that both subfoveal CVI and SFCT of the affected eye seemed relatively lower when compared with the fellow eye. Optical coherence tomography angiography showed reduced density of the choriocapillaris in the temporal area of the lesion and increased capillary density in the nasal area. Functional examinations, including microperimetry, multifocal electroretinogram and static perimetry also revealed reduced retinal sensitivity, decreased stimulated amplitude and suspected scotoma in the lesion area. After 12 months of follow-up, the patient's visual acuity and the clinical appearance of the lesion were unchanged.ConclusionThe torpedo maculopathy may be identified by abnormal appearance with multimodal imaging. Decreased choroidal vascularity in the lesion area measured quantitatively by choroid vascularity index may play a role in pathogenesis of torpedo maculopathy.

Project description:Torpedo maculopathy (TM) is a rare congenital defect of the retinal pigment epithelium (RPE). The RPE is often evaluated clinically using fundus autofluorescence (AF), a technique that visualizes RPE structure at the tissue level from the intrinsic AF of RPE fluorophores. TM lesions typically emit little or no AF, but this macroscopic assessment is unable to resolve the RPE cells, leaving the organization of the RPE cell mosaic in TM unknown. We used fluorescence adaptive optics scanning laser ophthalmoscopy (AOSLO) to show here for the first time the microscopic cellular-level structural alterations to the RPE cell mosaic in TM that underlie the tissue-level changes seen in conventional clinical imaging. We evaluated two patients with TM using conventional clinical imaging techniques and adaptive optics (AO) infrared autofluorescence (IRAF) in AOSLO. Confocal AOSLO revealed relatively normal cones outside the TM lesion but altered cone appearance within it and along its margins in both patients. We quantified cone topography and RPE cell morphometry from the fovea to the margin of the lesion in case 1 and found cone density to be within the normal range across the locations imaged. However, RPE morphometric analysis revealed disrupted RPE cells outside the margin of the lesion; the mean RPE cell area was greater than two standard deviations above the normative range up to approximately 1.5 mm from the lesion margin. Similar morphometric changes were seen to individual RPE cells in case 2. Multi-modal imaging with AOSLO reveals that RPE cells are abnormal in TM well beyond the margins of the characteristic TM lesion boundary defined with conventional clinical imaging. Since the TM fovea appears to be fully formed, with normal cone packing, it is possible that the congenital RPE defect in TM occurs relatively late in retinal development. This work demonstrates how cellular level imaging of the RPE can provide new insight into RPE pathologies, particularly for rare conditions such as TM.

Project description:PurposeQuantitative fundus autofluorescence (qAF) and spectral-domain optical coherence tomography (SD OCT) were performed in patients with bull's-eye maculopathy (BEM) to identify phenotypic markers that can aid in the differentiation of ABCA4-associated and non-ABCA4-associated disease.DesignProspective cross-sectional study at an academic referral center.SubjectsThirty-seven BEM patients (age range, 8-60 years) were studied. All patients exhibited a localized macular lesion exhibiting a smooth contour and qualitatively normal-appearing surrounding retina without flecks. Control values consisted of previously published data from 277 healthy subjects (374 eyes; age range, 5-60 years) without a family history of retinal dystrophy.MethodsAutofluorescence (AF) images (30°, 488-nm excitation) were acquired with a confocal scanning laser ophthalmoscope equipped with an internal fluorescent reference to account for variable laser power and detector sensitivity. The grey levels (GLs) from 8 circularly arranged segments positioned at an eccentricity of approximately 7° to 9° in each image were calibrated to the reference (0 GL), magnification, and normative optical media density to yield qAF. In addition, horizontal SD OCT images through the fovea were obtained. All patients were screened for ABCA4 mutations using the ABCR600 microarray, next-generation sequencing, or both.Main outcome measuresQuantitative AF, correlations between AF and SD OCT, and genotyping for ABCA4 variants.ResultsABCA4 mutations were identified in 22 patients, who tended to be younger (mean age, 21.9±8.3 years) than patients without ABCA4 mutations (mean age, 42.1±14.9 years). Whereas phenotypic differences were not obvious on the basis of qualitative fundus AF and SD OCT imaging, with qAF, the 2 groups of patients were clearly distinguishable. In the ABCA4-positive group, 37 of 41 eyes (19 of 22 patients) had qAF8 of more than the 95% confidence interval for age. Conversely, in the ABCA4-negative group, 22 of 26 eyes (13 of 15 patients) had qAF8 within the normal range.ConclusionsThe qAF method can differentiate between ABCA4-associated and non-ABCA4-associated BEM and may guide clinical diagnosis and genetic testing.

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Torpedo Maculopathy Associated with NEXMIF Mutation.

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Torpedo Maculopathy Associated with <i>NEXMIF</i> Mutation.

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